Skip to main content
SpringerLink
Log in

Change in the MGMT gene expression under the influence of exogenous cytokines in human cells in vitro

  • Published:
Cytology and Genetics Aims and scope Submit manuscript

Abstract

The influence of cytokines LIF, SCF, IL-3, and EMAP II and the Laferobion (IFN-a2b) drug on the MGMT gene expression in human cell cultures has been studied. It was shown that exogenous cytokines can modulate the MGMT gene expression at the protein level. EMAP II is able to increase or decrease the MGMT level, depending on the experimental conditions. Cytokines LIF, SCF, IL-3 and Laferobion decreased the MGMT expression level in human cells in vitro. Some conditions leading to the destruction of the MGMT protein complex were identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Margison, G., Povey, A., Kaina, B., and Santibáñez Koref, M., Variability and regulation of O6-alkylguanine-DNA alkyltransferase, Carcinogenesis, 2003, vol. 24, no. 4, pp. 625–635.

    Article  PubMed  CAS  Google Scholar 

  2. Fang, Q., Noronha, A.M., Murphy, S.P., et al., Repair of O6-G-alkyl-O6-G interstrand cross-links by human O6-alkylguanhine-dna alkyltransferase, Biochemistry, 2008, vol. 47, no. 41, pp. 10892–10903.

    Article  PubMed  CAS  Google Scholar 

  3. Kaina, B., Christmann, M., Naumann, S., and Roos, W., MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents, DNA Rep., 2007, vol. 6, pp. 1079–1099.

    Article  CAS  Google Scholar 

  4. Sabharwal, A. and Middleton, M.R., Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy, Curr. Opin. Pharm., 2006, vol. 6, pp. 355–363.

    Article  CAS  Google Scholar 

  5. Sharma, S., Salehi, F., Scheithauer, B.W., et al., Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis, Anticancer Res., 2009, vol. 29, no. 10, pp. 3759–3768.

    PubMed  CAS  Google Scholar 

  6. Verbeek, B., Southgate, T.D., Gilham, D.E., and Margison, G.P., O6-methylguanine-DNA methyltransferase inactivation and chemotherapy, Brit. Med. Bull., 2008, vol. 85, pp. 17–33.

    Article  PubMed  CAS  Google Scholar 

  7. Niture, S.K., Doneanu, C.E., Velu, C.S., et al., Proteomic analysis of human O6-methylguanine-DNA methyltransferase by affinity chromatography and tandem mass spectrometry, Biochem. Biophys. Res. Commun., 2005, vol. 337, pp. 1176–1184.

    Article  PubMed  CAS  Google Scholar 

  8. Natsume, A., Ishii, D., Wakabayashi, T., et al., IFN-β down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide, Cancer Res., 2005, vol. 65, no. 17, pp. 7573–7579.

    PubMed  CAS  Google Scholar 

  9. Rosati, S.F., Williams, R.F., Nunnally, L.C., et al., IFN-beta sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression, Mol. Cancer Ther., 2008, vol. 7, no. 12, pp. 3852–3858.

    Article  PubMed  CAS  Google Scholar 

  10. Zheng, M., Bocangel, D., Ramesh, R., et al., Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of O6-methylguanine-DNA methylransferase in human melanoma cells, Mol. Cancer Ther., 2008, vol. 7, no. 12, pp. 3842–3851.

    Article  PubMed  CAS  Google Scholar 

  11. Cardozo, A.K., Kruhoffer, M., Leeman, R., et al., Identification of novel cytokine-induced genes in pancreatic β-cells by high-density oligonucleotide arrays, Diabetes, 2001, vol. 50, pp. 909–920.

    Article  PubMed  CAS  Google Scholar 

  12. Motomura, K., Natsume, A., Kishida, Y., et al., Benefits of interferon-β and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter, Cancer, 2011, vol. 117, no. 8, pp. 1721–1730.

    Article  PubMed  CAS  Google Scholar 

  13. Briegert, M., Enk, A.H., and Kaina, B., Change in expression of MGMT during maturation of human monocytes into dendritic cells, DNA Rep., 2007, vol. 6, pp. 1255–1263.

    Article  CAS  Google Scholar 

  14. Ivakhno, S.S. and Kornelyuk, A.I., Cytokine-like activities of some aminoacyl-tRNA synthetases and auxiliary p43 cofactor of aminoacylation reaction and their role in oncogenesis, Exp. Oncol., 2004, vol. 26, no. 4, pp. 250–255.

    PubMed  CAS  Google Scholar 

  15. Schwarz, M.A., Kandel, J., Brett, J., et al., Endothelial-monocyte activating polypeptide II, a novel antitumour cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells, J. Exp. Mes., 1999, vol. 190, no. 3, pp. 341–354.

    Article  CAS  Google Scholar 

  16. Lylo, V.V., Matsevich, L.L., Kotsarenko, E.V., et al., Activation of gene expression of the O6-methylguanine-DNA transferase repair enzyme upon the influence of EMAP II cytokine in human cells in vitro, Cytol. Genet., 2011, vol. 45, no. 6, pp. 373–378.

    Article  Google Scholar 

  17. Dubrovsky, A.L., Brown, J.N., Kornelyuk, A.I., et al., Bacterial expression of full-length and truncated forms of cytokine EMAP-2 and cytokine-like domain of mammalian tyrosyl-tRNA synthetase, Biopolym. Cell, 2000, vol. 16, no. 3, pp. 229–235.

    Article  CAS  Google Scholar 

  18. Morton, E.N. and Margison, G.P., Increased O6-alkylguanine-DNA alkyltransferase activity in Chinese hamster V-79 cells following selection with chloroethylating agents, Carcinogenesis, 1988, vol. 9, no. 1, pp. 45–49.

    Article  Google Scholar 

  19. Laemmli, U.K., Cleavage of structural proteins during the assembly of the head of bacteriophage t4, Nature, 1970, vol. 227, no. 5259, pp. 680–685.

    Article  PubMed  CAS  Google Scholar 

  20. Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein-dye binding, Anal. Biochem., 1976, vol. 72, no. 1/2, pp. 248–254.

    Article  PubMed  CAS  Google Scholar 

  21. www.novusbio.com/MGMT-Antibody-MT-232_NB100-168.html

  22. Aldridge, G.M., Podrebarac, D.M., Greenough, W.T., and Weiler, I.J., The use of total protein stains as loading controls: an alternative to high-abundance single-protein controls in semi-quantitative immunoblotting, J. Neurosci. Meth., 2008, vol. 172, no. 2, pp. 250–254.

    Article  CAS  Google Scholar 

  23. Lylo, V.V., Identification of a modified form of the repair enzyme O6-alkylguanine-DNA alkyltransferase, Aktual. Probl. Akush. Ginekol. Klet. Biol. Med. Genet., 2010, vol. 19, pp. 299–305.

    Google Scholar 

  24. Kotsarenko, E.V., Lylo, V.V., Matseevich, L.L., et al., Cytokine LIF as a modulator MGMT gene expression in human cells in vitro, in Factors of Experimental Evolution of Organisms: Collected Scientific Papers, 2011, vol. 11, pp. 489–493.

    Google Scholar 

  25. Kotsarenko, E.V., Shaposhnik, L.A., Lylo, V.V., et al., Interferons as possible regulators of MGMT gene expression, Ukr. Biokhim. Zh., 2010, vol. 82, p. 35.

    Google Scholar 

  26. Pegg, A.E., Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools, Chem. Res. Toxicol., 2011, vol. 24, no. 5, pp. 618–639.

    Article  PubMed  CAS  Google Scholar 

  27. Blough, M.D., Zlatescu, M.C., and Cairncross, J.G., O6-methylguanine-DNA methyltransferase regulation by p53 in astrocytic cells, Cancer Res., 2007, vol. 67, no. 2, pp. 580–584.

    Article  PubMed  CAS  Google Scholar 

  28. Roos, W.P., Jost, E., Belohlavek, C., et al., Intrinsic anticancer drug resistance of malignant melanoma cells is abrogated by IFN-β and valproic acid, Cancer Res., 2011, vol. 71, no. 12, pp. 4150–4160.

    Article  PubMed  CAS  Google Scholar 

  29. De Veer, M.J., Holko, M., Frevel, M., et al., Functional classification of interferon-stimulated genes identified using microarrays, J. Leuk. Biol., 2001, vol. 69, no. 6, pp. 912–920.

    Google Scholar 

  30. Takaoka, A., Hayakawa, S., Yanai, H., et al., Integration of interferon-α/β signaling to p53 responses in tumour suppression and antiviral defense, Nature, 2003, vol. 424, pp. 516–523.

    Article  PubMed  CAS  Google Scholar 

  31. Traut, T.W., Dissociation of enzyme oligomers: a mechanism for allosteric regulation, Crit. Rev. Biochem. Mol. Biol., 1994, vol. 29, no. 2, pp. 135–163.

    Article  Google Scholar 

  32. Marianayagam, N.J., Sunde, M., and Matthews, J.M., The power of two: protein dimerization in biology, Trends Biochem. Sci., 2004, vol. 29, no. 11, pp. 618–625.

    Article  PubMed  CAS  Google Scholar 

  33. Henriksen, U., Fog, J.U., Litman, T., and Gether, U., Identification of intra- and intermolecular disulfide bridges in the multidrug resistance transporter ABCG2, J. Biol. Chem., 2005, vol. 280, no. 44, pp. 36926–36934.

    Article  PubMed  CAS  Google Scholar 

  34. Kolodziejski, P.J., Rashid, M.B., and Eissa, N.T., Intracellular formation of “undisruptable” dimmers of inducible nitric oxide synthase, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, no. 24, pp. 14263–14268.

    Article  PubMed  CAS  Google Scholar 

  35. Adams, C.A., Melikishvili, M., Rodgers, D.W., et al., Topologies of complexes containing O6-alkylguanine-DNA alkyltransferase and DNA, J. Mol. Biol., 2009, vol. 389, pp. 248–263.

    Article  PubMed  CAS  Google Scholar 

  36. Duguid, E.M., Rice, P.A., and He, C., The structure of the human AGT protein bound to DNA and its implications for damage detection, J. Mol. Biol., 2005, vol. 350, pp. 657–666.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

    K. V. Kotsarenko, V. V. Lylo, L. L. Macewicz, L. A. Babenko, A. I. Kornelyuk, T. A. Ruban & L. L. Lukash

Authors
  1. K. V. Kotsarenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. V. Lylo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. L. Macewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. A. Babenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. I. Kornelyuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. A. Ruban
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L. L. Lukash
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. L. Lukash.

Additional information

Original Russian Text © K.V. Kotsarenko, V.V. Lylo, L.L. Macewicz, L.A. Babenko, A.I. Kornelyuk, T.A. Ruban, L.L. Lukash, 2013, published in Tsitologiya i Genetika, 2013, Vol. 47, No. 4, pp. 9–18.

About this article

Cite this article

Kotsarenko, K.V., Lylo, V.V., Macewicz, L.L. et al. Change in the MGMT gene expression under the influence of exogenous cytokines in human cells in vitro. Cytol. Genet. 47, 202–209 (2013). https://doi.org/10.3103/S0095452713040087

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3103/S0095452713040087

Keywords

Search

Navigation